Dimethyl disulphide

Endpoint summary

Description of key information

In vivo studies in rabbits performed with DMDS according to the OECD 404 and 405 guidelines showed that DMDS was a mild irritant to the skin and was irritant to the eyes, respectively. In a study in which rats were exposed to DMDS vapours for a single 24 hour exposure, contact toxicity in the form of respiratory tract (nasal) irritation was identified and the NOAEC determined to be 12.5 ppm equivalent to 48.1 mg/m3.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Reference 1

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Deviations:

no

GLP compliance:

no

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: no data
- Age at study initiation: no data
- Weight at study initiation: 2.5 +/- 0.2 kg
- Housing: individually in polystyrene cage (540x360x315xmm)
- Diet : granulé Lapin entretien "112", UAR, ad libitum
- Water: ad libitum
- Acclimation period: 8 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): no data
- Humidity (%): no data
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light):no data

IN-LIFE DATES: 1985-02-26 To: 1985-02-29

Type of coverage:

semiocclusive

Preparation of test site:

shaved

Vehicle:

unchanged (no vehicle)

Controls:

not required

Amount / concentration applied:

0.5 ml

Duration of treatment / exposure:

4 hour(s)

Observation period:

72 hours

Number of animals:

6

Details on study design:

0.5 ml of the test substance, applied with a sterile polypropylene syringe of 2 ml, on a Codex hydrophilic eight layer gauze pad, about 2.5 cm square, previously laid down on the skin to avoid any loss of test substance. The gauze pad was held in contact with the skin with a semi-occlusive patch.

Irritation parameter:

erythema score

Basis:

mean

Time point:

24/48/72 h

Score:

1.78

Max. score:

4

Reversibility:

not fully reversible within: 72 h

Irritation parameter:

edema score

Basis:

mean

Time point:

24/48/72 h

Score:

1.22

Max. score:

4

Reversibility:

not fully reversible within: 72h

Individual and mean skin irritation scores

 

	Erythema/Oedema
Animal No	11000	11001	11002	11005	11010	11042
after 1 h	2 / 1	1/ 2	1 / 2	1 / 1	1 /1	2 / 2
after 24 h	2 / 2	2* / 1	2* / 2	2* / 2	2 / 2	2* / 2
after 48 h	2 / 1	2* / 1	2* / 2	1* / 1	2 / 1	2* / 2
after 72 h	1 / 0	2* / 1	2* / 1	1* / 0	1 / 0	2* / 1
mean score 24/48/72 h	1.67 / 1	2 / 1	2 / 1.67	1.33 / 1	1.67 / 1	2 / 1.67

*= reaction is seen beyond the area of application

 

Interpretation of results:

Category 3 (mild irritant) based on GHS criteria

Conclusions:

Dimethyl disulphide was slightly irritating. The effects were not fully reversible until the end of the observation period (72 hours).

Executive summary:

The acute dermal irritation of dimethyl disulphide (DMDS) was evaluated in rabbits according to OECD 404 guideline (Guillot, 1985). Dimethyl disulphide (purity 98.98%) was applied undiluted to the skin of 6 New-Zealand White albino rabbits and held in contact for 4 hours by means of a semi-occlusive dressing. Mean scores over 24, 48 and 72 hours were 1.78 and 1.22 for erythema and for edema, respectively. DMDS was considered as slightly irritating for the skin. In another study performed according to EPA 40 CFR 163.81-5 guideline (Shapiro, 1985). DMDS (purity unknown) was applied undiluted to the intact skin of 6 New-Zealand White albino rabbits and held in contact for 24 hours by means of an occlusive dressing. For the shaved skin, mean scores over 24, 48 and 72 hours were 1.03 and 0.11 for erythema and for edema, respectively. All lesions were reversible within 10 days. DMDS was considered as a mild irritant for the skin.

Reference 2

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Qualifier:

according to guideline

Guideline:

other: National Standard of the People’s Republic of China Toxicological Test Methods of Pesticides for Registration (GB 15670-1995)

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Deviations:

yes

Remarks:

study with 4 rabbits

GLP compliance:

yes (incl. QA statement)

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Covance Research Products Inc., Denver, PA, USA
- Age at study initiation: The male animals were born on 01 Nov 2014 and/or 22 Nov 2014 and the female animals were born on 01 Nov 2014 and/or 08 Nov 2014
- Weight at study initiation: 2.8 - 3.2 kg
- Housing: individually housed in suspended cages
- Diet: Fresh PMI Rabbit Chow (Diet #5321) was provided daily
- Water: ad libitum
- Acclimation period: at least one week

ENVIRONMENTAL CONDITIONS
No data

Type of coverage:

semiocclusive

Preparation of test site:

clipped

Vehicle:

unchanged (no vehicle)

Controls:

not required

Amount / concentration applied:

0.5 ml

Duration of treatment / exposure:

4 hours

Observation period:

0 and 60 minutes and at 24, 48 and 72 hours and on Days 4 through 6 in all four animals and on Days 7 through 14 for one animal

Number of animals:

4

Details on study design:

TEST SITE
- Area of exposure: 2.3 cm
- % coverage:
- Type of wrap if used: Porous, non-irritating tape

REMOVAL OF TEST SUBSTANCE
- Washing (if done): gently washing with distilled water
- Time after start of exposure:4h

Irritation parameter:

erythema score

Basis:

animal #1

Time point:

24/48/72 h

Score:

3

Max. score:

4

Reversibility:

fully reversible within: 6 days

Irritation parameter:

erythema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

1.66

Max. score:

4

Reversibility:

fully reversible within: 6 days

Irritation parameter:

erythema score

Basis:

animal #3

Time point:

24/48/72 h

Score:

2

Max. score:

4

Reversibility:

not fully reversible within: 14 days

Remarks:

score 1

Irritation parameter:

erythema score

Basis:

animal #4

Time point:

24/48/72 h

Score:

1.33

Max. score:

4

Reversibility:

fully reversible within: 6 days

Irritation parameter:

edema score

Basis:

animal #1

Time point:

24/48/72 h

Score:

2

Max. score:

4

Reversibility:

fully reversible within: 6 days

Irritation parameter:

edema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

1.66

Max. score:

4

Reversibility:

fully reversible within: 6 days

Irritation parameter:

edema score

Basis:

animal #3

Time point:

24/48/72 h

Score:

1.66

Max. score:

4

Reversibility:

fully reversible within: 6 days

Irritation parameter:

edema score

Basis:

animal #4

Time point:

24/48/72 h

Score:

1.66

Max. score:

4

Reversibility:

fully reversible within: 5 days

Other effects:

Systemic Observations: There were no abnormal physical signs observed.
Body Weight: Two animals gained body weight by study termination and two animals’ weight remained the same.

Interpretation of results:

Category 3 (mild irritant) based on GHS criteria

Conclusions:

Dimethyl disulfide is considered to be a mild irritant.

Executive summary:

The potential of Dimethyl Disulfide to cause skin irritation was evaluated when administered dermally to rabbits (Yasso, 2015). This study was designed to comply with the standards set forth in the National Standard of the People’s Republic of China Toxicological Test Methods of Pesticides for Registration (GB 15670-1995), which is comparable to the OECD TG 404. This study was conducted in accordance with the Good Laboratory Practices of the US EPA. Four healthy New Zealand White rabbits (two male - two female) were dosed dermally with Dimethyl disulfide. The test article (0.5 ml) was applied dermally to one intact site per rabbit and wrapped with a semi-occlusive dressing. The test article was kept in contact with the skin for 4 hours at which time the wrappings were removed. Erythema and edema were scored at 0 and 60 minutes and at 24, 48 and 72 hours and on Days 4 through 6 in all four animals and on Days 7 through 14 for one animal. The skin was also evaluated for ulceration and necrosis or any evidence of tissue destruction at these time periods. Animals were observed for mortality, toxicological and pharmacological effects at each dermal observation period. Body weights were recorded pretest and at termination. Erythema scores over 24, 48 and 72h were 3.0, 1.66, 2 and 1.33 for animals 1 to 4, respectively. Edema scores over 24, 48 and 72h were 2.0, 1.66, 1.66 and 1.66 for animals 1 to 4, respectively. All lesions were fully reversible within 6 days excepted an erythema score of 1 on one animal (#3) still present at the end (D14) of the observation period. There were no abnormal physical signs observed. Two animals gained body weight by study termination and two animals’ weight remained the same. Dimethyl disulfide is considered to be a mild irritant.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records

Reference

Reference 1

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Deviations:

no

GLP compliance:

no

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: no data
- Age at study initiation: no data
- Weight at study initiation: 2.5 +/- 0.2 kg
- Housing: individually in polystyrene cage (540x360x315xmm)
- Diet : granulé Lapin entretien "112", UAR, ad libitum
- Water: ad libitum
- Acclimation period: 8 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): no data
- Humidity (%): no data
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light):no data

IN-LIFE DATES: 1985-03-07 To: 1985-03-10

Vehicle:

unchanged (no vehicle)

Controls:

not required

Amount / concentration applied:

0.1 ml

Duration of treatment / exposure:

24 hour(s)

Observation period (in vivo):

72 hours

Number of animals or in vitro replicates:

6

Details on study design:

Comment: not rinsed

Irritation parameter:

conjunctivae score

Remarks:

enanthema

Basis:

mean

Time point:

24/48/72 h

Score:

1.33

Max. score:

3

Reversibility:

not fully reversible within: 72 h

Irritation parameter:

chemosis score

Basis:

mean

Time point:

24/48/72 h

Score:

1.89

Max. score:

4

Reversibility:

not fully reversible within: 72 h

Irritation parameter:

iris score

Basis:

mean

Time point:

24/48/72 h

Score:

1

Max. score:

2

Reversibility:

not fully reversible within: 72 h

Irritation parameter:

cornea opacity score

Basis:

mean

Time point:

24/48/72 h

Score:

0.83

Max. score:

4

Reversibility:

not fully reversible within: 72 h

Interpretation of results:

Category 2A (irritating to eyes) based on GHS criteria

Conclusions:

Dimethyl disulphide is considered as irritating for the eyes.

Executive summary:

The potential of dimethyl sulphide to induce ocular irritation was evaluated in rabbits according to OECD (No. 405) guideline. A single dose of 0.1mL of the undiluted test item was instilled into the conjunctival sac of the eye of 6 rabbits. The eyes were not rinsed after administration of the test item.

Ocular reactions were observed approximately 1 hour, 24, 48 and 72 hours after the administration. Mean scores calculated over 24, 48 and 72 hours were 1.89 for chemosis, 1.33 for redness of the conjunctiva, 1.00 for iris lesions and 0.83 for corneal opacity. Under these experimental conditions, dimethyl disulphide was irritant when administered by ocular route to rabbits.

Reference 2

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

other information

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: GLP guideline study but the DMDS tested in this study did not correspond to the specifications of DMDS proposed for registration (high level of methyl mercaptan).

Qualifier:

according to guideline

Guideline:

other: EPA-40 CFR 163-81-4

Deviations:

no

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ORGANISMS:
- Source: Davidson's Mill Farm, S. Brunswick, NJ
- Age: no data
- Weight at study initiation: 2.3-3.0 kg
- Adaptation period: 7 days
- Number of animals: 4 males + 5 females 

HOUSING
The animals were housed individually in wire bottomed cages

FOOD and WATER
- Food: Purina rabbit pellets, ad libitum
- Water: ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature : 68-72°F
- Relative humidity : no data
- Light/dark cycle : 12h/12h
- Ventilation : no data

Vehicle:

unchanged (no vehicle)

Controls:

not required

Amount / concentration applied:

0.1 ml

Duration of treatment / exposure:

not rinced for 6 rabbits, rinced after 20-30 sec. for 3 rabbits

Observation period (in vivo):

21 days

Number of animals or in vitro replicates:

9 (6 not rinced, 3 rinced)

Irritation parameter:

conjunctivae score

Remarks:

Unwashed

Basis:

mean

Time point:

24/48/72 h

Score:

1.32

Max. score:

3

Reversibility:

fully reversible within: 7 days

Irritation parameter:

chemosis score

Remarks:

Unwashed

Basis:

mean

Time point:

24/48/72 h

Score:

1

Max. score:

4

Reversibility:

fully reversible within: 7 days

Irritation parameter:

cornea opacity score

Remarks:

Unwashed

Basis:

mean

Time point:

24/48/72 h

Score:

0.33

Max. score:

4

Reversibility:

fully reversible within: 7 days

Irritation parameter:

iris score

Remarks:

Unwashed

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

2

Irritation parameter:

conjunctivae score

Remarks:

Washed

Basis:

mean

Time point:

24/48/72 h

Score:

0.66

Max. score:

3

Reversibility:

fully reversible within: 72 h

Irritation parameter:

chemosis score

Remarks:

Washed

Basis:

mean

Time point:

24/48/72 h

Score:

0.44

Max. score:

4

Reversibility:

fully reversible within: 72 h

Irritation parameter:

iris score

Remarks:

Washed

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

2

Irritation parameter:

cornea opacity score

Remarks:

Washed

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritant / corrosive response data:

Corneal opacity was observed in the unwashed eyes of 2 rabbits. The  opacity was transient and disappeared by 7 days. Transient hyperemia and chemosis were also observed in all rabbits (washed and un washed eyes). These conditions disappeared  between 24 and 96 hours post instillation. No iridial damage was noted in any of the rabbits.

Interpretation of results:

GHS criteria not met

Conclusions:

Dimethyl Disulphide is considered to be slightly irritating to both the unwashed and the washed eye.

Executive summary:

The potential of dimethyl sulphide to induce ocular irritation was evaluated in rabbits according to EPA-40 CFR 163-81-4 guideline. A single dose of 0.1mL of the undiluted test item was instilled into the conjunctival sac of the eye of 9 rabbits. The eyes were for 6 rabbits or rinced after 20-30 sec. for 3 rabbits after administration. Ocular reactions were observed approximately 1 hour, 24, 48 and 72 hours after the administration. Corneal opacity was observed in the unwashed eyes of 2 rabbits. The  opacity was transient and disappeared by 7 days. Transient hyperemia and chemosis were also observed in all rabbits (washed and un washed eyes). These conditions disappeared  between 24 and 96 hours post instillation. No iridial damage was noted in any of the rabbits.

Mean scores calculated over 24, 48 and 72 hours for the unwashed eyes were 1.0 for chemosis, 1.33 for redness of the conjunctiva, 0.0 for iris lesions and 0.33 for corneal opacity. Under these experimental conditions, dimethyl disulphide was considered slightly irritating to the eyes.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Additional information

Skin irritation

The potential of Dimethyl Disulfide to cause skin irritation was evaluated when administered dermally to rabbits (Yasso, 2015). This study was designed to comply with the standards set forth in the National Standard of the People’s Republic of China Toxicological Test Methods of Pesticides for Registration (GB 15670-1995), which is comparable to the OECD TG 404. This study was conducted in accordance with the Good Laboratory Practices of the US EPA. Four healthy New Zealand White rabbits (two male - two female) were dosed dermally with Dimethyl disulfide. The test article (0.5 ml) was applied dermally to one intact site per rabbit and wrapped with a semi-occlusive dressing. The test article was kept in contact with the skin for 4 hours at which time the wrappings were removed. Erythema and edema were scored at 0 and 60 minutes and at 24, 48 and 72 hours and on Days 4 through 6 in all four animals and on Days 7 through 14 for one animal. The skin was also evaluated for ulceration and necrosis or any evidence of tissue destruction at these time periods. Animals were observed for mortality, toxicological and pharmacological effects at each dermal observation period. Body weights were recorded pretest and at termination. Erythema scores over 24, 48 and 72h were 3.0, 1.66, 2 and 1.33 for animals 1 to 4, respectively. Edema scores over 24, 48 and 72h were 2.0, 1.66, 1.66 and 1.66 for animals 1 to 4, respectively. All lesions were fully reversible within 6 days excepted an erythema score of 1 on one animal (#3) still present at the end (D14) of the observation period. There were no abnormal physical signs observed. Two animals gained body weight by study termination and two animals’ weight remained the same. Dimethyl disulfide is considered to be a mild irritant.

The acute dermal irritation of dimethyl disulphide (DMDS) was evaluated in rabbits according to OECD 404 guideline (Guillot, 1985). Dimethyl disulphide (purity 98.98%) was applied undiluted to the skin of 6 New-Zealand White albino rabbits and held in contact for 4 hours by means of a semi-occlusive dressing. Mean scores over 24, 48 and 72 hours were 1.78 and 1.22 for erythema and for edema, respectively. DMDS was considered as slightly irritating for the skin. In another study performed according to EPA 40 CFR 163.81-5 guideline (Shapiro, 1985). DMDS (purity unknown) was applied undiluted to the intact skin of 6 New-Zealand White albino rabbits and held in contact for 24 hours by means of an occlusive dressing. For the shaved skin, mean scores over 24, 48 and 72 hours were 1.03 and 0.11 for erythema and for edema, respectively. All lesions were reversible within 10 days. DMDS was considered as a mild irritant for the skin.

 

Eye irritation

The potential of dimethyl sulphide to induce ocular irritation was evaluated in rabbits according to OECD (No. 405) guideline (Guillot, 1985). A single dose of 0.1mL of the undiluted test item (purity 98.98%) was instilled into the conjunctival sac of the eye of 6 rabbits. Mean scores calculated over 24, 48 and 72 hours were 1.89 for chemosis, 1.33 for redness of the conjunctiva, 1.00 for iris lesions and 0.83 for corneal opacity. Dimethyl disulphide was considered as irritant when administered by ocular route to rabbits.

The potential of Dimethyl Disulfide to cause eye irritation was evaluated when administered to rabbits (Hall, 2015). This study was designed to comply with the standards set forth in the National Standard of the People’s Republic of China Toxicological Test Methods of Pesticides for Registration (GB 15670-1995), which is comparable to the OECD 405. This study was conducted in accordance with the Good Laboratory Practices of the US EPA. Four healthy New Zealand White rabbits (two males - two females), free from evidence of ocular irritation and corneal abnormalities, were placed on the study. An analgesic, Buprenorphine was administered subcutaneously between the shoulder blades approximately 1.5 hours prior to instillation of the test article. A dose of 0.1 ml of Dimethyl disulfide was placed into the conjunctival sac of one eye of each rabbit. The eyes were examined pretest and scored by the Draize technique at 1, 24, 48 and 72 hours post-dose. The control eyes were observed at the same time periods. Sodium fluorescein dye procedures were used at the 24-hour observation interval for all four animals and in one animal at the 48-hour observation interval. Observations for mortality, toxicity and pharmacological effects were recorded at each ocular observation period. Body weights were recorded immediately pretest and at termination. There was no corneal opacity or iritis noted at any time point. Conjunctival irritation, noted in four out of four eyes, cleared in one eye by 48 hours and in three eyes by 72 hours. The control eyes appeared normal at all time points. Over 24, 48 and 72h, corneal opacity and iris scores were 0 for the 4 rabbits, conjunctival scores were 0.66 for rabbits 1 and 2, 1.0 for rabbit 3 and 0.33 for rabbit 4 and chemosis scores were 0.33 for rabbits 1 and 3 and 0 for rabbits 2 and 4. One animal was noted with diminished feed consumption and one animal was noted with soiling of the anogenital area. Two animals lost weight and two animals’ weights remained the same. Under these experimental conditions, dimethyl disulphide was considered slightly irritating to the eyes.

 

Respiratory tract irritation

See sections acute inhalation toxicity (Kirkpatrick, 2008 and 2009) and repeated dose inhalation toxicity (Collins, 1992; Nemec, 2006).

Justification for classification or non-classification

Based on the available data, DMDS is classified as Eye irritating Category 2 (H319) according to the Regulation EC n°1272/2008.

Justification for the eye irritation classification :

In the key study (Guillot, 1985b), effects meeting the CLP criteria for eye irritation category 2 (a mean score of ≥1 for iritis and a mean score of ≥2 for conjunctival chemosis calculated following grading at 24, 48 and 72 hours after installation of the test material at least in 2 of 3 tested animals) were observed in tested animals. The reversibility of the effects was not assessed in this study, but the value of individual eye irritation scores had a declining trend over time. In supporting studies by Shapiro (1985e) and Hall (2015), the effects had fully reversed in 7 days and 48-72 hours, respectively, although the mean scores observed in these studies did not meet the CLP criteria for Eye Irrit. 2; H319.
Considering all the available evidence, RAC concludes that DMDS warrants classification as Eye Irrit. 2, H319 (Causes serious eye irritation).

 

Justification for the absence of skin irritation classification (RAC conclusion):

Since in the acceptable study, Guillot (1985a), the CLP criteria for skin irritation were not fulfilled, RAC considers that DMDS does not warrant classification for skin corrosion/irritation. Although the reversibility of effects was not examined for the 14 day period recommended in the TG, the findings are assumed to be reversible, since their intensity was not very high (below criteria for classification) and in the study of Shapiro (1985) similar skin responses were fully reversible within 10 days.
The results of the study performed according to the EPA 40 CFR 163.81-5 guideline by Shapiro (1985) is in line with the results of Guillot (1985a). In this study, the mean scores from skin gradings at 24, 48 and 72 hours after patch removal did not reach 2.3 or higher for erythema/eschar or for oedema in any animal.
Since the slightly irritating skin effects observed in both studies did not meet the classification criteria (≥ 2.3 for oedema or erythema), and although the reversibility of the effects in Guillot (1985a) was not investigated, because similar skin responses in the study by Shapiro (1985) were fully reversible in 10 days, RAC is of the opinion that no classification is warranted for skin irritation.